Mitochondria are dynamic organelles that alter their organization in response to a variety of cellular cues. Mitochondria are central in many biologic processes, such as cellular bioenergetics and apoptosis, and mitochondrial network morphology can contribute to those physiologic processes. Some of the biologic processes that are in part governed by mitochondria are also commonly deregulated in cancers. Furthermore, patient tumor samples from a variety of cancers have revealed that mitochondrial dynamics machinery may be deregulated in tumors. In this review, we will discuss how commonly mutated oncogenes and their downstream effector pathways regulate the mitochondrial dynamics machinery to promote changes in mitochondrial morphology as well as the physiologic consequences of altered mitochondrial morphology for tumorigenic growth.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers. Uncovering mechanisms responsible for the heterogeneous clinical features of this disease is an essential step toward developing improved and more specific therapeutic approaches. Here, we sought to identify transcriptional regulators of aggressive PDAC growth through in vivo CRISPR screening of epigenetic and transcription factors in an orthotopic model. We identified the ISL LIM homeobox 2 ( ISL2 ) gene as a tumor suppressor whose depletion enhances the proliferation of human PDAC cells in vitro and in vivo and cooperates with activated KRAS to initiate PDAC in a murine model. Conversely, the upregulation of ISL2 expression through CRISPR-mediated locus-specific epigenetic editing results in reduced cell proliferation. Importantly, ISL2 is epigenetically silenced through DNA methylation in ~60% of PDAC tumors, which correlates with poor patient outcome. Functional studies showed that ISL2 loss rewires metabolic gene expression, and consequently potentiates oxidative phosphorylation while reducing glycolysis. This metabolic shift creates selective vulnerability to small molecule inhibitors of mitochondrial respiration and fatty acid oxidation. Collectively, these findings reveal ISL2 as a novel tumor suppressor whose inactivation drives metabolic reprogramming in an aggressive PDAC subset and point to potential therapeutic vulnerabilities in these tumors.

Pancreatic cancer is the third leading cause of cancer-related death in the US. First-line chemotherapy regimens for pancreatic ductal adenocarcinoma (PDAC) include FOLFIRINOX or gemcitabine (Gem) with or without paclitaxel (Ptx); however, 5-year survival with these regimens remains poor. Previous work has demonstrated protein arginine methyltransferase 5 (PRMT5) to be a promising therapeutic target in combination with Gem for the treatment of PDAC; however, these findings have yet to be confirmed in relevant preclinical models of PDAC. To test the possibility of PRMT5 as a viable therapeutic target, clinically relevant orthotopic and metastatic patient-derived xenograft (PDX) mouse models of PDAC growth were utilized to evaluate the effect of PRMT5 knockout (KO) or pharmacologic inhibition on treatment with Gem alone or Gem with Ptx. Primary endpoints included tumor volume, tumor weight, or metastatic tumor burden as appropriate. The results showed that Gem-treated PRMT5 KO tumors exhibited decreased growth and were smaller in size compared to Gem-treated wild-type (WT) tumors. Similarly, the Gem-treated PRMT5 KO metastatic burden was lower than the Gem-treated WT metastatic burden. The addition of a PRMT5 pharmacologic inhibitor to Gem and Ptx therapy resulted in a lower final tumor weight and fewer metastatic tumors. The depletion of PRMT5 results in increased DNA damage in response to Gem and Ptx treatment. Thus, PRMT5 genetic depletion or inhibition in combination with Gem-based therapy improved the response in primary and metastatic PDAC in clinically relevant mouse models, suggesting that PRMT5 is a viable therapeutic target for combination therapy in PDAC.

miR-206 , miR-1a-1 and miR-1a-2 are induced during differentiation of skeletal myoblasts and promote myogenesis in vitro . miR-206 is required for skeletal muscle regeneration in vivo . Although this microRNA family is hypothesized to play an essential role in differentiation, a triple knockout of the three genes has not been done to test this hypothesis. We report that triple KO C2C12 myoblasts generated using CRISPR/Cas9 method differentiate despite the expected de-repression of the microRNA targets. Surprisingly, their mitochondrial function is diminished. Triple KO mice demonstrate partial embryonic lethality, most likely due to the role of miR-1a in cardiac muscle differentiation. Two triple KO mice survive and grow normally to adulthood with smaller myofiber diameter and diminished physical performance. Thus, unlike other microRNAs important in other differentiation pathways, the miR-206 family is not absolutely essential for myogenesis and is instead a modulator of optimal differentiation of skeletal myoblasts.